Structure of negative allosteric modulator-bound inactive human calcium-sensing receptor
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ABSTRACT:
SUBMITTER: Qing Rong Fan
PROVIDER: EMPIAR-10835 | biostudies-other |
REPOSITORIES: biostudies-other
Publications
Symmetric activation and modulation of the human calcium-sensing receptor.
Park Jinseo J Zuo Hao H Frangaj Aurel A Fu Ziao Z Yen Laura Y LY Zhang Zhening Z Mosyak Lidia L Slavkovich Vesna N VN Liu Jonathan J Ray Kimberly M KM Cao Baohua B Vallese Francesca F Geng Yong Y Chen Shaoxia S Grassucci Robert R Dandey Venkata P VP Tan Yong Zi YZ Eng Edward E Lee Yeji Y Kloss Brian B Liu Zheng Z Hendrickson Wayne A WA Potter Clinton S CS Carragher Bridget B Graziano Joseph J Conigrave Arthur D AD Frank Joachim J Clarke Oliver B OB Fan Qing R QR
Proceedings of the National Academy of Sciences of the United States of America 20211201 51
The human extracellular calcium-sensing (CaS) receptor controls plasma Ca<sup>2+</sup> levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS receptor corrects disorders of calcium homeostasis. Here, we report the cryogenic-electron microscopy reconstructions of a near-full-length CaS receptor in the absence and presence of allosteric modulators. Activation of the homodimeric CaS receptor requires a break in the transmembrane 6 ...[more]
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| EMPIAR-10834 | biostudies-other
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Project description:Background and purposeNegative allosteric modulators (NAMs) that target the calcium-sensing receptor (CaS receptor) were originally developed for the treatment of osteoporosis by stimulating the release of endogenous parathyroid hormone, but failed in human clinical trials. Several chemically and structurally distinct NAM scaffolds have been described, but it is not known how these different scaffolds interact with the CaS receptor to inhibit receptor signalling in response to agonists.Experimental approachIn the present study, we used a mutagenesis approach combined with analytical pharmacology and computational modelling to probe the binding sites of four distinct NAM scaffolds.Key resultsAlthough all four scaffolds bind to the 7-transmembrane and/or extracellular or intracellular loops, they occupy distinct regions, as previously shown for positive allosteric modulators of the CaS receptor. Furthermore, different NAM scaffolds mediate negative allosteric modulation via distinct amino acid networks.Conclusion and implicationsThese findings aid our understanding of how different NAMs bind to and inhibit the CaS receptor. Elucidation of allosteric binding sites in the CaS receptor has implications for the discovery of novel allosteric modulators.
| S-EPMC7070164 | biostudies-literature
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| S-EPMC4856764 | biostudies-literature
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| S-EPMC4621983 | biostudies-literature
Project description:Negative allosteric modulators (NAMs) of the human calcium-sensing receptor (CaSR) have previously failed to show efficacy in human osteoporosis clinical trials, but there is now significant interest in repurposing these drugs for hypocalcemic disorders and inflammatory lung diseases. However, little is known about how CaSR NAMs inhibit the response to endogenous activators. An improved understanding of CaSR negative allosteric modulation may afford the opportunity to develop therapeutically superior CaSR-targeting drugs. In an attempt to elucidate the mechanistic and structural basis of allosteric modulation mediated by the previously reported NAM, calhex231, we herein demonstrate that calhex231 actually potentiates or inhibits the activity of multiple CaSR agonists depending on whether it occupies one or both protomers in a CaSR dimer. These findings reveal a novel mechanism of mode-switching at a Class C G protein-coupled receptor that has implications for drug discovery and potential clinical utility.
| S-EPMC7089027 | biostudies-literature
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| S-EPMC6177624 | biostudies-literature
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